The newfound relationship between extrachromosomal DNAs and excised signal circles

Elevated levels of extrachromosomal DNAs (ecDNAs) are associated with poor prognoses of many cancer types. These large circular DNAs typically harbour oncogenes and regulatory elements which, together with high levels of ecDNA transcription, confer a growth advantage to cancer cells. Replication of ecDNAs, followed by their unequal distribution at mitosis, further promotes rapid cancer evolution. In contrast to ecDNAs, the role of circular DNA by-products from V(D)J recombination in cancer development has largely been overlooked. Developing lymphocytes generate millions of excised signal circles (ESCs) each day through gene rearrangement at the immunoglobulin and T-cell receptor loci. Despite their similar size to ecDNAs, ESCs were long assumed to be inert and lost during cell division. However, it is now known that ESCs potently trigger genome instability when complexed with recombinase proteins. Not only this, but new data show that just like ecDNAs, ESCs replicate and persist, with high levels strongly correlating with poor prognosis of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Despite these striking similarities, the properties of ESCs and ecDNAs are seldom linked. Here, we provide the first comparative review of ecDNAs and ESCs, and highlight the reasons why these molecules are more closely related than once assumed.